By Robert Cohen Executive Director Text Only

AA = Autism & ADD


SCIENTIFIC PROOF: MILK CAUSES AUTISM & ADD

Florida researcher, Robert Cade, M.D., and his colleagues have identified a milk protein, casomorphin, as the probable cause of attention deficit disorder and autism. They found Beta-casomorphin-7 in high concentrations in the blood and urine of patients with either schizophrenia or autism.

(AUTISM, 1999, 3)


Eighty percent of cow's milk protein is casein. It has been documented that casein breaks down in the stomach to produce a peptide casomorphine, an opiate.

Another researcher observed that casomorphin aggravated the symptoms of autism.

(Panksepp, J. Trends in Neuroscience, 1979, 2)


A third scientist produced evidence of elevated levels of endorphin-like substances in the cerebro-spinal fluid of people with autism.

(Gillberg, C. (1988) Aspects of Autism: Biological Research Gaskell:London, pp. 31-37)


The Autism Research Unit, School of Health Sciences has the following information on their website:

"The quantities of these compounds, as found in the urine, are much too large to be of central nervous system origin. The quantities are such that they can only have been derived from the incomplete breakdown of certain foods."

http://osiris.sunderland.ac.uk/autism/


PARENT'S MAGAZINE REPORTS MILK LINK TO AUTISM

Search the Internet and you'll find many anecdotal stories from parents blaming their children's autism on milk and dairy products. One such story appeared in the February, 2000 issue of "Parent's Magazine."

http://www.livingsensibly.org/autism.html


See references 25 to 33
____________________

A Chemical Aetiology for Autistic Spectrum Disorders:
Opioid Peptides and Secretin
Unpublished Paper by Stephen Dealler

http://trainland.tripod.com/stephen.htm

The suggestion that the syndrome of autism was similar in psychological
terms to that seen in children who had received morphine was put forward
by Panksepp in 1978 (1). The reason as to how this might take place in
vivo when no morphine was being administered and no poppy derived
products were present in their diet was initially unclear. The finding
that casomorphins produced a reduction in distress by chicks when
separated from others (2) was considered as evidence.

Increased levels of a group of urinary peptides were found
(3,4,5,6,7,8,9) and demonstrated by gel filtration, HPLC, and SDS-PAGE
electrophoresis (10) These results were not found in the urine of
children with the fragile X syndrome (4) and a different profile of
peptide sizes was seen in late onset infantile autism, neonatal-onset
infantile autism, and mixed onset cases including atypical ones (4).
False-positive urinary profiles were found in 5-7% of controls and false
negative ones in 5% (n=126) over 12 years. It has been known for some
time that if peptidases are lacking in the gut then there is an increase
in peptides found in the urine (11) but no histopathological changes
have been reported in autism and no absolute lack of peptidases. It is
suggested, however that the mechanism by which the peptides enter the
blood is as a result of the lack of activity of two specific peptidases
(4) as this fits with the genetic rate for the disease in siblings.
There had been some indication of gut abnormality in that an excess of
cases of coeliac disease was found (4) by one group and indications of
malabsorption in others (12,13,14,15). Good research has shown that
there is an abnormal intestinal permeability in children with autism
(16) and hence the uptake of these peptides is not necessarily the
result of the lack of specific peptidases at all.

The hypotheses as to why opioid peptides should act to produce an
autistic syndrome have been fully described in a chemical manner
(6,17,18,19,20) but inadequate information is available to be certain of
the mechanisms described.

It was discovered that these individual peptides may have opioid
activity (21,22,23) and certainly had biological activity of some kind
(24). The finding that some had opioid-like receptor binding (24,25) was
followed up by the finding that bovine casomorphins, opioid peptides
from milk, were present in urine and dialysis fluid (4,25). It is known
that casomophins and gluteomorphins are produced in the gut by
proteinase digestion of milk and wheat proteins (26,27,28) and that
casomorphins can have been involved in post partum psychosis (29) and
hence penetrate the CNS (30).

An increase in IgA antibodies was found in the blood of autistic
children against gluten and casein (4) but in 4 of the 44 children no
such antibodies were found whatever. This made the value of immune
testing difficult to understand: there might have been a large enough
absorption for the IgA to have interacted with the peptides and taken
out of the circulation or only a small uptake; in which case antibodies
were formed but are of little significance.

When put onto a diet without milk or gluten-containing foods it can be
shown that peptide excretion decreases in the urine from around
30mmol/24hrs to around 10mmol/24hrs (4,31) and when the diet was stopped
the peptide excretion increased to previous levels.

When first started on this diet, it was noted that some of the children
showed a change in their psychological activity and were 'cold turkey'
at some points over the first few days, suggesting an opioid withdrawal
effect. Autistic patients put on a diet without gluten or milk protein
improved clinically (4,5,31,32,33) and this was shown using
psychological tests, tests of teaching, and indications by parents.
Although it is difficult to explain the figures used to describe the
improvement without understanding the mechanism, it is clear that an
improvement did take place.

A diet of this kind is difficult to maintain and a number of patients
withdrew from the studies after having shown an improvement. These
patients showed a slow regression to the previous condition (4)

Autistic children (12) were tested with naltrexone, a long acting opiate
inhibitor, in a double blind controlled trial and showed an overall
improvement in their condition. The partial agonist activity of
naltrexone was a problem in that higher doses appeared to have a lesser
effect than lower ones (34). Also, the naltrexone did not alter the
behaviour of the patient simply by decreasing all autistic action but
rather by modifying certain ones. A reduction in stereotypies,
increasing in verbal production, an improvement in social behaviour and
self-injurious behaviour. Other, open trial studies, showed similar
results (35-42). Overall the results were not as great as were hoped and
when naltrexone was stopped, previous behaviour returned.

It has been suggested that the long term exposure of the brain to
peptide morphines from the diet would have a trophic effect on the brain
in the same way as morphine itself (28,29,43) and that this may explain
the progressive nature of autism in some cases; giving rise to an
increase in epileptic fits and EEG abnormalities in increasing age (44).
The long term endorphins and naltrexone were separately shown to modify
the development of the brain (17,45). No research has been carried out
currently to see what effect long term removal of these diet-derived
peptides may have and whether any of the damage may recover. There have
been individual reports of epilepsy ceasing following the removal of
specific factors from the diet but the mechanisms are unclear.

Secretin

Secretin is a 27 amino acid polypeptide discovered in 1902 by Bayliss
and Starling (46). Compared to other neuropeptides it has been poorly
researched, with publications reaching a peak between 1980 and 1985
(47). Its aminoacid sequence was not found until 1965 (48) because of
the low quantities that were present to test. However it was first
synthesised shortly afterwards (49). The structure turned out to be well
retained through evolution; both beef and porcine (50) secretin differed
from human secretin by 2 amino acids and dog secretin differed by a
single one (51). When formed in the rat it is made as a precursor
protein intracellularly from a 739 base gene, of which only 692 bases
are expressed as mRNA (52). The precursor protein exists as a signal
peptide, an amino terminal peptide, secretin, and a carboxy terminal
peptide. The signal, amino and carboxy terminal peptides are cleaved
from secretin before its release. This precursor and gene are identical
in the duodenum and in the brain.

Secretin is one of a group of neuropeptides that were originally felt to
be found only in the gut and to act as endocrines. All of them have
been found to be present in the brain also. They are known as the
secretin group of peptides (table 1). This is important as research into
all of these has been greater than into secretin itself (7) and certain
factors from this research are expected to be significant for secretin.

This group of neuropeptides is remarkable in that, although they are
similar in structure, they have often quite different activities and
different receptors in tissues. Some of them will cross react between
receptors but the cross reaction is minimal in vivo despite this
similarity (52a). It is likely that evolutionary change has demanded
specific action even as a result of small changes in the peptide
structure. As a result it would be expected that only small changes in
secretin structure would decrease its activity but possibly not alter
its assay using standard radio-immunoassay techniques. Because of this
it is essential that if any assay of secretin is undertaken, it is
necessary to test the activity of the hormone and its structure: not
just the presence of the peptide.

Secretin mode of action

Secretin interacts with highly specific cellular surface receptors which
carry intracellularly a Gs type protein which then changes the action
of
certain cellular enzymes. Human secretin receptors belong to a seven-
transmembrane domain subfamily that includes receptors for VIP, PACAP
and glucagon. The receptor structures have been well worked out (53) as
being generally around 1616 bases (54) in length (53) and distinct
receptors were characterized in the guinea pig pancreatic acini (54),
rat gastric glands (55), rat cholangiocytes (56), mouse neuroblastoma
cells (57), and mouse-rat NG108-15 neuroblastoma-glioma hybrid cells
(58). The rat secretin receptor (RSR) cDNA was the first to be worked
out as a member of a distinct new family of G protein-coupled receptors
(59) that now include VIP (60,61,62), PACAP (63,64,65), glucagon
(66,67), parathyroid hormone (68) and calcitonin (69). It can be shown
that rat and human receptors are similar; being closely homologous
except at the amino and carboxy terminals (53). The main action seen is
the increase in adenyl cyclase activity and it is thought that this is
the major mode of action of secretin both in the periphery and in the
central nervous system. There is also an increase in calcium inside the
affected cell and an increase in inositol phosphate production. A
modified form of secretin has been shown to act as an antagonist in vivo
in rodents due to its ability to interact with the receptor but in some
way not stimulate its activity (49)

Secretin activity in the periphery

Secretin is only produced peripherally by the S cells of the proximal
section of the duodenum and acts as a feed back loop used to counter the
stomach acid arriving there after food. The presence of acidic fluid in
the duodenum or the distension of it causes secretin release. This is
passed though the circulation to acinar cells of the pancreas where it
causes an increase in the release of alkali. It causes an increase in
fluid release from the biliary system, the small intestine epithelium
and the pancreas. It decreases the production of gastric acid, gastrin
(69), but increases the release of pepsinogen from gastric chief cells.
Some cardiac and renal activity is seen but this has not been fully
investigated. Secretin also causes an increase in the activity of
tyrosine hydroxylase (TH) in cervical ganglion neurones and
phaeochromocytoma cells (70,71). This enzyme is the limiting section of
the manufacture of catecholamines (e.g. adrenaline) and hence it is felt
that some adrenergic activity may be seen as a result but it has not
been quantified.

TH activity has been shown to be subject to the regulation by the cAMP
system inside the cell as well as calcium and cGMP second messenger
systems (70). Treatment of intact rat PC12 cells with neuropeptides
including secretin stimulated TH activity 2 to 3 fold (71).

This activity is not surprising in that receptors for secretin have been

found to be present in the pancreas, kidney, rat gastric glands,
cholangiocytes, neuroblastoma cells, neuroblastoma glioma cells, lung,
and intestinal epithelium. All of these appear to have more receptor
activity than that seen in brain, heart or ovary. However no receptors
at all are seen in other tissues tested. Cross reactivity between the
secretin group peptides has been seen but to a low degree. Measured KD
levels were 10-7 to 10-10 mol.

In neonatal animal experimental secretin has been shown to be involved
in the growth and development of the gut, stomach and pancreas (72,73).

Secretin activity in the brain

The quantity of secretin in neurological tissues seems to be similar to
that in the duodenum, varying between 7pg/mg (wet weight) of the cortex
to 130 pg/mg of the pineal (74) (table 2).

It was first demonstrated in the brain of the rat and pig (but not in
the guinea pig)(75). Highest levels were found in the medulla oblongada,
thalamus, hypothalamus olfactory bulb, hippocampus, midbrain, cerebellum
and brain stem (74,80) Initially there was difficulty in demonstrating
that this was correct and researchers failed

to repeat the findings. However the demonstration of mRNA for the
precursor peptide in similar quantities to that found in the duodenum in
the same tissue ratios as found for the secretin itself means that this
can no longer be open to argument.

Like other transmitters such as dopamine, the action of peptides may be
through the stimulation of adenylate cyclase thus increasing levels of
cyclic AMP to cause intracellular changes rather than alterations in
transmembrane potentials (70,76,77) as is seen with acetyl choline.

Specific activity has been shown by secretin: inhibition of prolactin
and leutinising hormone release; displacement of VIP from certain
receptors; increase the turnover and level of dopamine; increase in
adenyl cyclase activity in the hypothalamus; glycogenolysis in primary
culture glial cells; enhancement of pancreatic volume and bicarbonate
response to acid in the duodenum (this was shown not to be a systemic
effect of secretin escaping from the intracerebral inoculation of the
drug into the blood) (78)

Penetration of the blood brain barrier

One of the major questions in this field has been whether or not
secretin and other neuropeptides could be used as therapeutic agents.
Around 50% that have been tested have been found to cross the blood
brain barrier easily and rapidly with levels appearing in the CSF within
5 minutes of peripheral inoculation (79). Secretin has not been tested
in this respect but, as all of the other members of the group seem to
penetrate the BBB, it is unlikely that it is not true for secretin (80).

The finding that i.v. secretin caused a rapid increase in prolactin
whereas i.c. it caused a decrease, has suggested that there is a short
negative feed back loop present and that this probably is taking place
in the hypothalamus. This also suggests that the BBB is penetrated by
secretin and reaches some specifically sensitive site. Further work must
be carried out into this, however.

It should also be remembered that intraventricularly administered
peptides also appear rapidly in the blood (81) although, again this
experiment was not carried out with secretin.

Lack of secretin activity as a potential cause of the gut uptake and
inadequate breakdown of opioid peptides in autistics

The genetic aspects of autism suggest that either two gene abnormalities
are required or, as there is a 36%-91% correalation in monozygotic twins
(82,83,84) it would suggest an approximately 50% penetration of a single
gene. The finding of a dizygotic sibling concordance rate of 3% is
similar to that seen in a condition that required two recessive
alterations (6.3%), rather than the 50% penetration of a single one,
which would appear in 12.5%.

The finding that the gut in autistics may be abnormal in that it takes
up long chain molecules (16), may suggest that it is not so much the
peptidase acitivity that is inadequate but that there is a physiological
barrier between the gut and the blood that is ineffective. This has
been shown with carbohydrates and with peptides.

It has been shown that secretin is relatively high in the blood of
neonates (72,73) and that infusions of it causes precocious cessation of
intestinal macromolecular transmission (72).

The clinical effect seen from secretin in autism is strange in that the
action has been reported as descriptions from patients' relatives to
increase for several days after a single intravenous injection and the
effect is seen to reach a peak between 2 and 4 weeks. This cannot be
simply due to the effect of secretin on the brain as a neurotransmitter
as the half-life of compound is short. This long term effects suggested
would fit better with secretin as an inducer of protein production or
cellular maturation. causing an alteration in cells that would either be
themselves destroyed or lose the action gradually. Although secretin
when inoculated intrecerebrally was shown to induce morphine action,
this effect did not last for long periods and hence cannot be thought of
as the specific cause of the phenomenon in autism (85). For instance,
one hypothesis could be that the action of the injected secretin may be
as an inducer of changes in the gut epithelium cells that are themselves
lost by shedding over the following weeks.

If secretin was seen to prevent the pathological gut physiology seen in
some autistic children then this effect might be seen if inadequate
secretin was being produced by the S cells of the duodenum or if the
secretin that was produced did not interact adequately with the receptor
molecules (this might be found if only small changes were made). Some
autistic cases may not respond at all to secretin and either the
mechanism by which it would act was faulty (e.g. the secretin receptors)
or some other pathology was present to which secretin was not
significant. Also, it must be remembered that alterations in the
receptor may give rise to inadequate action taking place on the G-
protein and from there a lack of change in cellular adenyl cyclase
activity.

If this chain of action gave rise to the lack of secretin physiology in
the autistic child, then it would not be found that all would respond to

injected hormone. Only those in which the secretin was missing or
altered would improve. Any cases in which it was either the receptor or
its mode of action that were ineffective would not respond.

Psychology

It may also be worth discussing how, in psychological terms, disruptions
of opioid mechanisms might lead to the symptoms of autism. There is
convincing evidence that autistic spectrum disorders are associated with
what are termed theory-of-mind problems (86, 87, 89). This means that
autistic children appear unable to comprehend the mental states of other
people or appreciate their perspectives. This specific pattern of
psychological problems is associated with other, still quite specific,
problems with what is termed central executive functioning (90,88). A
convincing argument can be developed to the conclusion that specific
deficits in central executive functioning, probably the ability
simultaneously to process more than two pieces of information, lead to
the problems observed in autistic spectrum disorders. It is entirely
possible that secretin and other opioid peptides mediate these
processes.

Discussion

The reports that secretin appears to improve a group of autistic
children and that this takes place over a period much greater than it
would be expected due to its short term action as a neurotransmitter and
to induce the release of alkali into the duodenum. The long term
hormonal action of secretin has been poorly investigated but may involve
gut development. The finding that secretin inoculated into 3 autistic
children (91) caused an excessively large increase in alkali secretion
would be consistent with there being inadequate secretin present
normally. While the long term hormonal actions of secretin are
inadequately studied, further research needs to be carried out
concerning autism; first to see if secretin has adequate action in
autism at all (92) but if it does, however small, to follow its mode of
action as a key to the physical and chemical pathology of the condition
as yet poorly understood.

92 References:

1. Panksepp J, Normansell L, Siviy St, Diruibe VA, Abbou-Issa H.
Potential biochemical markers for infantile autism. Neurochem Pathol
1986;5:51-70.
2. Panksepp. A neurochemical theory of autism. Trends Neurosci
19789;2:174-177.
3. Reichelt KL, Hole K, Hamberger A, Saelid G, Edminson PD,
Braestrup CB, Lingjaerde O, Ledaal P, Orbeck H. Biologically active
peptide-containing fractions in schizophrenia and childhood autism.
Neurosecretion and Brain Peptides. Ed: JB Martin, S. Reichlin and KL
Bick. Raven Press, New York 1981. 627-643
4. Reichelt KL, Knivsberg AM, Lind G, Nodland M. Probable etiology
and possible treatment of childhood autism. Brain dysfunct
1991;4:308-319.
5. Reichelt KL, Knivsberg AM, Nodland M, Lind G. Nature and
consequences of hyperpeptiduria and bovine casomorphins found in
autistic syndrome. Dev Brain Dysfunction 1994;7:71-85.
6. Shattock P, Kennedy A, Rowell F, Berney T. Role of neuropeptides
in autism and their relationships with classical neurotransmitters.
Brain Dysfunction 1990;3:328-345.
7. Shattock P, Savery D. Evaluation of urinary profiles obtained from
people with autism and associated disorders. Part 1: Classification of
subgroups. In: Proceedings of conference on Living and Learning with
Autism: Perspectives from the Individual, the Family and the
Professional, April 1997 199-208.
8. Shattock P, Savery D. Urinary profiles of people with autism:
Possible implications and relevance to other research. In: Procedings
of Conference on Therapeutic Interventions in Autism: Perspectives
from Research and Practice. April 1996 309-325.
9. Gilberg C, Trygstad O, Fossi I. Childhood psychosis and urinary
exretion of peptides and protein-associated peptide complexes. J
Autism Dev Disord 1982;12:229-41.
10. Williams K, Shattock P, Berney T. Proteins, peptides and autism.
Part 1: Urinary protein patterns in autism as revealed by sodium
dodecyl sulphate-polyacrylamide gel electrophoresis and silver
staining.Brain dysfunction 1991;4:320-322.
11. Mahe S, Tome D, Dumontier AM, Deseux JF. Absorption of intact
morphiceptin by diisopropyl fluorophosphate-treated rabbit ileum.
Peptides 1989;10:45-52.
12. Coleman M. Calcium studies and their relationship to coeliac
disease in autistic patients. In: Colerman M (ed). Autistic
Syndromes. Amsterdam North Holland Press. 1976. 197-205.
13. Goodwin MS, Cowen MA, Goodwin TC. Malabsorption and cerebral
dysfunction. A multivariate and comparative study of autistic children.
J Autism Child Schizophr 1971;1:48-62.
14. Shattock P. Autism: Possible clues to the underlying pathology. A
parent's view: in: Wing L (ed) Aspects of Autism. Biological Research.
London, Gaskell 1988, 11-18.
15. Fung BP, Rongo A, Leiter AB. Genetic ablation of secretin cells in
transgenic mice reveals lineage relationsips between multiple
endocrine cell types in the small intestine. Gastroenterology AGA
Abstracts 1994;110(4):A1112.
16. D'Eufemia P, Celli M, Finocchiaro R, Pacifico L, Viozzi L,
Zaccagnini M, Cardi E, Giardini O. Abnormal intestinal permeability in
children with autism. Acta Paeiatrica 1996;85:1076-9.
17. Shattock P, Lowdon G. Proteins, peptides and autism. Part 2.
Implications for the education and care of people with autism. Brain
Dysfunction 1991;4:323-334.
18. Gillberg C. The role of endogenous opioids in autism and the
possible relationships to clinical features. In: Wing L (ed) Aspects of
Autism: Biological Research. London, Gaskell, 1988, 31-37.
19. Reichelt KL, Scott H, Knivsberg AM, Wiig K, Lind G, Nodland M.
Childhood autism: A group of hyperpeptidergic disorders. Possible
etiology and tentative treatment: In Nyberg F, Brantl V (eds)
Beta=Casomorphins and Related Peptides. Uppsala, Eyris-Tryck AB,
1990, 163-173.
20. Gillberg C. Theoretical considerations: CNS mechanisms
underlying the autistic syndrome. In Coleman M, Gillberg C (eds)
The Biology of the Autistic Syndromes. New York, Praeger, 1985
197-206.
21. Reichelt KL, Saelid G, Lindback T, Boler JB. Childhood autism: A
complex disorder. Biol Psychiatry 1986;21:1279-1290.
22. Shattock P. Role of neuropeptides in autism and their
relationships with classical neurotransmitters. Brain Dysfunction
1990;3:328-346.
23. Israngkun PP, Newman HA, Patel ST, Duruibe VA, Abou-Issa H.
Potential biochemical markers for infantile autism. Neurochem Pathol
1986;5:51-70.
24. Reichelt KL, Knivsberg AM, Nodland M, Pedersen OS. Correlation
of found bioactivities with symptoms typical of autistic syndromes. In
Proceedings of conference on Biological Perspectives in Autism. April
1993 65-83.
25. Reichelt KL, Knivsberg AM, Nodland M, Lind G. Nature and
consequence of hyperpeptiduria and bovine casomorphine found in
autistic syndromes. Brain Dysfunction 1994;7:71-85.
26. Zioudrou C, Streaty RA, Klee WA. Opioid peptides derived from
food proteins. J Biol Chem 1979;254:2446-9.
27. Swedberg J, de Haas J, Leimanstoll G, Paul F, Teschemacher H.
Demonstration of beta-casomorphin immunoreactive materials in
vitro digests of bovine milk and in small intestine contents after
bovine milk ingestion in adult humans. Peptides 1985;6:825-831.
28. Umbach H, Teschemacher H, Praetorius K, Hirschhauser R,
Bostedt H. Demonstration of beta-casomorphin immunoreactive
material in the plasma of newborn calves after milk intake. Regul
Pept 1985;12:223-230.
29. Linstrom LH, Nyberg F, Terenius L, Bauer K, Besev G, Gunne LM,
Lyrens S, Willdeck-Lund GJ, Lundberg B. CSF and plasma
beta-casomorphin-like opioid peptides in post-partum psychosis. Am
J Psychiatry 1984;141:1059-66.
30. Hemmings WA. The entry into the brain of large molecules
derived from dietary protein. Proc R Soc Lond (Biol)
1978;200:175-192.
31. Whiteley P, Rodgers J, Savery D, Shattock P. A gluten-free diet
as an intervention for autism and associated spectrum disorders:
Preliminary findings. Autism 1999;3:45-65.
32. Knivsberg AM, Wiig K, Lind G, Nodland M, Reichelt KL. Deitary
intervention in autistic syndromes. Brain Dysfunction
1990;3:315-327.
33. Knivsberg AM, Reichelt KA, Nodland M, Hoien T. Autistic
syndromes and diet: a follow-up study. Scandinavian Journal of
Educational Research 1995;39:223-236.
34. Scifo R, Batticane N, Quattropani MC, Spoto G, Marchetti B. A
double-blind trial with naltrexone in autism. Brain Dysfunction
1991;4:301-307.
35. Herman BH, Hammock MK, Arthur-Smith A, Egan J, Chatoor I,
Werner A, Zelnick N. Naltrexone decreases self-injurous behaviour.
Ann Neurol 1987;22:550-552.
36. Lensing PJ. Two single studies with naltrexone. Acts Conf:
Experimental Psychology and The Austistic Syndromes, Durham,
1990 67-93.
37. Leboyer M, Bouvard M, Dugas M. Effects of naltrexone in infantile
autism. Lancet 1988;i:715.
38. Leboyer M, Bouvard M, Lensing P, Launa JM, Tabuteau F, Waller
D, Plumet MH, Recasens C, Kerdelhue B, Dugas M, Panksepp J. The
opiod excess hypothesis of autism: A double blind study of
naltrexone. Brain Dysfunction 1990;3:285-298.
39. Campbell M, Overall JE, Small A, Sokol MS, Spencer E, Adams P,
Foltz R, Monti K, Perry R, Nobler M, Roberts E. Naltrexone in autistic
children: An acute open dose range tolerance trial. J Am Acad Child
Adolesc Psychiatry 1989;28:200-206.
40. Lensing PJ, Klinger D, Gerstl W, Panksepp J. Clinical notes on
naltrexone therapy for five autistic children. Provisional guidelines
for
future research. Acts Conf: Experimental Psychology and The Autistic
Syndromes, Durham 1989 219-232.
41. Campbell M, Perry R, Small A, McVeigh-Tesch L, Curren E.
Naltrexone in infantile autism. Psychopharmacol Bull
1988;24:135-139.
42. Panksepp J, Lensing P, Leboyer M, Bouvard MP. Naltrexone and
other potential new pharmacological treatments of autism. Brain
Dysfunction 1991;4:281-300.
43. Zagon IS, McLaughlin PJ. Endogenous opioid systems regulate
cell proliferation in the developing rat brain . Brain re
1987;412:68-72
44. Deykin EY, Macmhon N. The incidence of seizures among children
with autistic syndromes. Am J Psychiatry 1979;136:1310-12.
45. Shattock P, Kennedy A, Rowell F, Berney T. Role of
neuropeptides in autism and their relationships with classical
neurotransmitters. Brain Dysfunction 1990;3:328-334.
46. Bayliss WM, Starling EH. The mechanism of pancreatic secretion.
J. Physiol (London) 1902;28:325-53.
47. Myers RD. Neuroactive peptides: Unique phases in research on
mammalian brain over three decades. Peptides 1994;15:367-381.
48. Mutt V, Magnussion S, Jorpes JE. Structure of porcine secretin. 1.
Degradation with trypsin and thrombin. Sequence of the tryptic
peptides. The C-terminal residue. Biochemistry 1965;4:2358-67.
49. Bodanszky M, Ondetti MA, Levine SP, Williams NJ. Synthesis of
secretin. II The stepwise approach. J Am chem Soc
1964;89:6753-6757.
50. Nishitani J, Lopez MJ, Leiter AB. Transcriptional regulation of
secretin gene expression. J Clin gastroenterol 1995;21(suppliment
1):S50-55.
51. Shinomura V, Eng J, Yalow RS. Dog secretin: sequence and
biological activity. Life Sciences 1987;41:1243-48.
52. Itoh N, Furaya T, Ozaki K, Ohta M, Kawasaki T. The secretin
precursor gene. J Biol Chem. 1991;266:12595-12598.
52a Chieweiss H, Glowinski J, Premont J. Do secretin and vasoactive
intestinal peptide have independent receptors on striatal neurons
and glial cells in primary cultures? Journal of Neurochemistry
1986;47:608-613.
53. Patel DR, Kong Y, Sreedharan P. Molecular cloning and
expression of a human secretin receptor. Molecular Pharmacology
1995;47:467-73.
54. Haffar BM, Hocart SJ, Coy DH, Mantey S, Chiang HV, Jensen RT.
Reduced peptide bond pseudopeptide analogues of secretin: a new
class of secretin receptor antagonists. J. Biol. chem. 1991;266:322.
55. Bawab W, Gespach C, Marie JC, Chastre E, Rosselin G.
Pharmacology and molecular identification of secretin receptors in rat
gastric glands. Life Sci. 1988;42:791-798.
56. Kato A, Gores GJ, LaRusso NF. Secretin stimulates exocytosis in
isolated bile duct epithelial cells by a cyclic AMP mediated
mechanism. J Biol Chem. 1992;267:15523-15529.
57. Roth BL, Beinfeld MC, Howlett AC. Secretin receptors on
neuroblastoma cell membranes:characterization of 125I-labelled
secretin binding and association with adenylate cyclase. J Neurochem.
1984;42:1145-1152.
58. Gossen D, Tastenoy M, Robberecht P, Christophe J. Secretin
receptors in the neuroglioma hybrid cell line NG108-15:
characterization and regulation of their expression. Eur J Biochem
1990;193:149-154.
59. Ishihara T, Nakamura S, Kaziro Y, Takahashi T, Takahashi K,
Nagata S. Molecular cloning and expression of a cDNA encoding the
secretin receptor. EMBO J 1991;10:1635-41.
60. Sreedharan SP, patel DR, Huang J, Goetzl EJ. Cloning and
functional expression of a human neuroendocrine vasoactive
intestinal peptide receptor. Biochem Biophys Res Commun
1993;193:546-553.
61. Lutz EM, Sheward WJ, West KM, Morrow JA, Fink G, Harmar AJ.
The VIP(2) receptor: molecular characterization of a cDNA encoding a
novbel receptor for VIP. FEBS Lett 1993:334:3-8.
62. Inagaki N, Yoshida H, Mizuta M, Mizuno N, Fujii Y, Gonoi T,
Miyazaki J, Seino S. Cloning and functional characterisation of a third
PACAP receptor subtype expressed in insulin-secreting cells. Proc Natl
Acad Sci USA 1994;91:2679-2683.
63. Pisegna JR, Wank SA. Molecular cloning and functional
expression of the PACA: type I receptor. Proc Natl Acad Sci USA
1993;90:6345-6349.
64. Hashimoto H, Ishihara T, Shigemoto R, Mori K, Nagata S.
Molecular cloning and tissue distribution of a receptor for PACAP.
Neuron 1993;11:333-342.
65. Spengler D, Waeber C, Pantaloni C, Holsboer F, Bockaert J,
Seeburg PH, Journot L. Differential signal transduction by five splice
variants of the PACAP receptor. Nature (London) 1993;365:170-175.
66. Jelenek LJ, Lok S, Rosenburg GB et al. Expression cloning and
signalling properties of the rat glucagon receptor. Science
(Washington DC) 1991;254:1024-1026.
67. MacNeil DJ, Occi JL, Hey PJ, Strader CD, Graziano MP. Cloning
and expression of a human glucagon receptor. Biochem Biophys Res
Commun 1994;198:328-334.
68. Juppner JA, Abou-Samra AB, Freeman M, Kong X, Shipani E,
Kolakowski LF, Hock J, Potts JT, Kronenberg HM, Segre GV. A
G-protein linked receptor for parathyroid homone and parathyroid
homone-related peptide. Science (Washington DC)
1991;254:1024-1026.
69. Lin HY, Harris TL, Flannery MS, Aruffo A, Kaji EH, Gorn A,
Kolakowski LF, Lodish H, Goldring SR. Expression ofan
adenylate-cyclase-coupled calcitonin receptor. Science (Washington
DC) 1991;254:1022-1024.
70. Fremeau RT, Korman LY, Moody TW. Secretin stimulates cyclic
AMP formation in the rat brain. J Neurochem 1986;46:1947-55.
71. Roskoski R, White L, Knowlton R, Roskoski LR. Regulation of
tyrosine hydroxylase activity in rat PC12 cells by neuropeptides of the
secretin family. Pharmacology 1989;36:925-931.
72. Harada E, Syuto B. Secretin induces precocious cessation of
intestinal macromolecular transmission and maltase development in
the suckling rat. Biol neonate 1993;63:52-60.
73. Pollack PF, Wood JG, Solomon T. Effect of secretin on growth of
stomach, small intestine, and pancreas of developing rats. digestive
Diseases and Sciences 1990;35:749-58.
74. Samson WK, Lumpkin MD, McCann SM. Presence and possible
site of action of secretin in the rat pituitary and hypothalamus. Life
Sciences 1984;34:155-163.
75. O'Donohue TL, Charlton CG, Miller RL, Boden G, Jacobowitz DM.
Identification, characterization and distribution of secretin
immunoreactivity in rat and pig brain. Proc Natl Acad Sci USA
1981;78:5221-4.
76. Chneiweiss H, Glowinski J, Pridont J. Vasoactive intestinal
po;ypeptide receptors linked to an adenylate cyclase, and their
relationship with biogenic amine- and somatostatin-sensitive
adenylate cyclases on central neuronal and glial cells in primary
cultures. J neurochem 1985;779-786.
77. Van Calker D, Muller M, Hamprecht B. Regulation of secretin,
vasoactive intestinal peptide and somatostatin of cyclic AMP
accumulation in cultures brain cells. Proc Natl Acad Sci USA
1980;77:6907-11.
78. Conter RL, Hughes MT, Kauffman GL. Intracerebroventricular
secretin enhances pancreatic volume and bicarbonate response in
rats. Surgery 1996;119:208-213.
79. Banks WA, Kastin AJ. Peptide transport systems for opiates
across the blood-brain barrier. Am J Physiol 1990;259:E1-10.
80. Banks WA, Kastin AJ, Garzone PD, Colburn WA, Mokotoff M. Eds.
Regulation of the passage ofpeptides across the bloo-brain barrier.
In Pharmacokinetics and Pharmacodynamics, Vol 3. Peptides,
Peptoids, and Proteins. Harvey Whitney Books. Cincinnati. 1991
147-153.
81. Passaro EP, Debas H, Oldendorf W, Yamada T. Rapid
appearance of intraventricularly administered neuropeptides in the
peripheral circulation. Brain Res 1982;241:335-340.
82. Folstein S, Rutter M. Infantile autism: A genetic study of 21 twin
pairs. J Child Psychol Psychiatry 1977;18:297-331.
83. Steffenburg S, Gillberg C, Hellgren L, Andersson L, Gillberg I,
Jakobsson G, Bohman M. A twin study of autism in Denmark,
Finland, Iceland, Norway and Sweden. J Child Psychol Psychiatry
1989;30:405-416.
84. Smalley S, Asarmow R, Spence M. Autism and genetics: A decade
of reseearch. Arch Gen Psychiatry 1988;45:953-961.
85. Babarczy E, Szabo G, Telegdy G. Effect of secretin on acute and
chronic effects of morphine. Pharmacology Biochemistry and
Behaviour 1995;51:469-72.
86. Baron-Cohen, S. (1995). Mindblindness: An essay on autism and
theory of mind. Cambridge, Mass.: MIT Press.
87. Happé, F., 1:9-15.
92. Owley T, Steel E, Corsello C et al. A dougle blind,
placebo-controlled trial of secretin for the treatment of autism.
Medscape General Medicine 6th October 1999.

For children with autism, milk may very well be the major factor. One out of five American children have been diagnosed with attention deficit disorder. One out of five American children take Ritalin. An alternative therapy? NOTMILK!



Robert Cohen author of:   MILK A-Z
(201-871-5871)
Executive Director (notmilkman@notmilk.com)
Dairy Education Board
http://www.notmilk.com



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